This proposal is directed toward the total synthesis of macrocyclic natural products of the cembrane and pseudopterane families of diterpenoids. Certain of the cembrane targets possess antimicrobial and antiprotozoal activity. Several are cytotoxic and show antineoplastic activity toward P- 388 lymphocytic leukemia. Recent findings have shown that some cembrane alcohols are highly effective inhibitors of phorbol ester promoted tumors. The pseudopteranes are a relatively new class of marine natural products with a promising range of biological activities. Pseudopterolide is a potent neurotoxin and the kallolides show high anti-inflammatory activity and low toxicity. The synthetic routes to be explored in this project will focus on the efficient assemblage of homochiral acyclic precursors and the development of methodology for their macrocyclization. Selective transformations of the resultant macrocyclic intermediates will also be examined. Studies on macrocyclization and chemical manipulations of macrocylic intermediates will be aided by molecular mechanics calculations and x-ray structure analysis.